Comparative Effectiveness of Two Initial Combination Therapies in Patients With Recent Onset Diabetes

Phase 3

Recruiting

• Conditions: Type 2 Diabetes (Adult Onset)
• Interventions: Drug: Tirzepatide; Drug: Sitagliptin; Drug: Metformin HCI XR; Drug: Pioglitazone

• Registration Number: NCT06246799
• Lead Sponsor: The University of Texas Health Science Center at San Antonio

Brief Summary

The primary purpose of this study is to evaluate the efficacy, durability, and mechanism of HbA1c reduction produced by the combination of pioglitazone plus tirzepatide compared to metformin plus sitagliptin in patients with recently diagnosed type 2 diabetes mellitus.

Detailed Description

This is a randomized open label controlled 2 arm study (with one of the arms containing 3 sub-groups) which aims to examine the effectiveness and long term effects on HbA1c reduction produced by the combination of pioglitazone plus tirzepatide versus metformin plus sitagliptin in recently diagnosed type 2 diabetes mellitus (T2DM) patients.

A subgroup of patients from group 1 will be invited to participate in a sub-study which lasts for 6 months and aims at exploring the metabolic/molecular mechanisms responsible for the study results. The selection of subjects to each subgroup will be done randomly and the end of sub-study, subjects will continue therapy and follow-up from month 6 on in the main study.

Study Timeline

• Study First Submitted: 2024-01-30
• Study First Submitted QC: 2024-01-30
• Study First Posted: 2024-02-07
• Study Start: 2024-11-07
• Status Verified: 2025-02
• Last Update Submitted: 2025-02-20
• Last Update Posted: 2025-02-24
• Primary Completion: 2029-04-30
• Study Completion: 2029-06-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 256

Inclusion Criteria

1. Ability of subject to understand and the willingness to sign a written informed consent document.
2. Males and females; Age 18-75 years
3. Recently (within 5 years) diagnosed Type 2 Diabetes Mellitus (T2DM) patients
4. Drug naïve or receiving metformin monotherapy
5. HbA1c >6.5% (no limit on upper HbA1c value);
6. Willingness to adhere to the investigational product regimen
7. Good general health
8. Stable body weight over the preceding 3 months
9. Agreement to adhere to Lifestyle Considerations throughout study duration.

Exclusion Criteria

1. positive anti-GAD (antibodies to glutamic acid decarboxylase)
2. pregnancy or plan of becoming pregnant
3. evidence of proliferative diabetic retinopathy,
4. plasma creatinine >1.4 females or >1.5 males;
5. presence of congestive heart failure (CHF);
6. history of cancer (<5 years);
7. prior history of pancreatitis,
8. bladder cancer or family history of thyroid tumors;
9. presence of hematuria in the urine analysis.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group IA	Tirzepatide	Tirzepatide will be started at 2.5mg and increased to 15mg by month 4. At month 6, Pioglitazone will be added to the Tirzepatide, 15 mg daily.
Group IC	Tirzepatide	Tirzepatide starting at 2.5mg weekly titrated to 15mg weekly (2.5 month 1, 5mg month 2, 10mg month 3 and 15mg at month 4) with Pioglitazone beginning at 15mg daily and ending at 45mg daily (15mg month 1, 30mg month 2 and 45mg at month 3 onwards).
Group II	Metformin HCI XR	Metformin starting at 1000mg XR daily and Sitagliptin 100mg daily at week 4, Metformin will be increased to 200mg.
Group IC	Pioglitazone	Tirzepatide starting at 2.5mg weekly titrated to 15mg weekly (2.5 month 1, 5mg month 2, 10mg month 3 and 15mg at month 4) with Pioglitazone beginning at 15mg daily and ending at 45mg daily (15mg month 1, 30mg month 2 and 45mg at month 3 onwards).
Group II	Sitagliptin	Metformin starting at 1000mg XR daily and Sitagliptin 100mg daily at week 4, Metformin will be increased to 200mg.
Group 1B	Pioglitazone	Pioglitazone will be started at 15mg and increased to 45 mg by month 3. At month 6, tirzepatide 2.5mg will be started and increased weekly as tolerated.
Group IA	Pioglitazone	Tirzepatide will be started at 2.5mg and increased to 15mg by month 4. At month 6, Pioglitazone will be added to the Tirzepatide, 15 mg daily.
Group 1B	Tirzepatide	Pioglitazone will be started at 15mg and increased to 45 mg by month 3. At month 6, tirzepatide 2.5mg will be started and increased weekly as tolerated.

Primary Outcome Measures

Name	Time	Method
Number of subjects failing to achieving HbA1c <6.5% Long-term	month 60	The failure to achieving HbA1c \<6.5% (Durability) at the end of study in subjects receiving pioglitazone/tirzepatide (Group I) versus metformin/sitagliptin (Group II) in two consecutive HbA1c measurements 3 months apart.
number of subjects achieving HbA1c <6.5% at 6 months (Efficacy)	6 months	Therapy failure will be determined as HbA1c \>6.5% in two consecutive HbA1c measurements 3 months apart. Time to cumulative incidence of therapy failure curves will be created in subjects receiving pioglitazone/tirzepatide versus subjects receiving metformin/sitagliptin

Secondary Outcome Measures

Name	Time	Method
Change in insulin sensitivity	from baseline to end of study (60 months)	Matsuda Index of insulin sensitivity or total glucose disposal measured with the clamp.These are the gold standard methods for quantification insulin sensitivity with the OGTT or a euglycemic clamp
Change in body weight	Baseline to end of study (60 months)	Change from study beginning to end, measured in kilograms (kg)
Change in Beta Cell Function	Baseline to end of study (60 months)	A calculated value using plasma glucose, insulin and C-peptide concentrations during the Oral Glucose Tolerance Test (OGTT) test.

Trial Locations

Locations (2)

University Health System Texas Diabetic Institute; 🇺🇸 San Antonio, Texas, United States

UT Health Science Center; 🇺🇸 San Antonio, Texas, United States